Antidiabetic piperazine derivatives, processes for their preparation and compositions containing them

ABSTRACT

Piperazine derivatives of formula (I)                    
     wherein 
     Z, X, n, Ar and i have the meanings defined herein are usefull in the treatment of pathologies associated with insulin-resistance syndrome.

The present invention relates to novel piperazine derivatives which areof use in the treatment of pathologies associated withinsulin-resistance syndrome.

The compounds of the invention have the formula:

in which:

n represents 2, 3, 4, 5 or 6;

X represents O or S;

Ar represents an aromatic nucleus chosen from phenyl, pyridyl,pyrimidinyl, benzoxazolyl, benzothiazolyl and benzimidazolyl, the saidaromatic nucleus optionally being substituted by one or more radicalschosen from a halogen atom; a (C₁-C₆) alkoxy group; a (C₆-C₁₀) aryloxygroup; a (C₆-C₁₀)aryl(C₁-C₆)alkoxy group in which the aryl part isoptionally substituted by halogen, (C₁-C₆)alkyl or (C₁-C₆)alkoxy; and a(C₁-C₆)alkyl group substituted by one or more halogen atoms;

i represents 0, 1, 2, 3 or 4; and

each Z group independently represents a halogen atom; as well as theiraddition salts with pharmaceutically acceptable bases or acids.

The invention also relates to the solvates of the compounds of formulaI.

The term “alkyl” is understood to mean, according to the invention, alinear or branched hydrocarbon-comprising group. Mention may be made, asexample of alkyl groups, of the methyl, ethyl, propyl, n-butyl,isobutyl, sec-butyl, tert-butyl, isoamyl, tert-amyl, sec-amyl, pentyland hexyl groups.

The alkyl parts of the alkoxy and arylalkoxy groups have the samedefinition as given above for the alkyl group.

Mention may be made, as example of alkyl groups substituted by one ormore halogen atoms, of the perfluoroalkyl groups, such astrifluoromethyl or pentafluoroethyl.

The aryl group is a mono- or polycyclic aromatic group, preferably mono-or bicyclic, such as phenyl or naphthyl. The same definition is validfor the aryl parts of the aryloxy and arylalkoxy groups.

The halogen atoms are chosen from bromine, fluorine, iodine andchlorine.

When Ar represents substituted phenyl, the phenyl nucleus can carry one,two, three, four or five substituents. However, when Ar representssubstituted phenyl, the phenyl nucleus is preferably mono-, di- ortrisubstituted. In this case, the substituents are preferably in themeta or para position.

Examples of preferred aryloxy groups are phenoxy and naphthyloxy.

An example of a preferred arylalkoxy group is the benzyloxy group.

The —CH₂—COOH group of the compounds of the invention is situated eitherin the ortho position or in the meta position or in the para positionwith regard to the chain

However, preference is given to the compounds in which the —CH₂—COOHgroup is in the para or ortho position, the para position beingespecially preferred.

The compounds of formula I have a carboxyl functional group and can besalified. They are then provided in the form of addition salts withorganic or inorganic bases.

The addition salts with bases are, for example, pharmaceuticallyacceptable salts, such as the sodium salts, the potassium salts or thecalcium salts, which are obtained by using the corresponding alkalimetal or alkaline earth metal hydroxides as bases.

Mention may be made, as other types of addition salts withpharmaceutically acceptable bases, of the salts with amines and inparticular glucamine, N-methylglucamine, N,N-dimethylglucamine,ethanolamine, morpholine, N-methylmorpholine or lysine.

The compounds of formula I can also be salified with inorganic ororganic acids and preferably pharmaceutically acceptable acids, such ashydrochloric acid, phosphoric acid, fumaric acid, citric acid, oxalicacid, sulphuric acid, ascorbic acid, tartaric acid, maleic acid,mandelic acid, methanesulphonic acid, lactobionic acid, gluconic acid,glucaric acid, succinic acid, sulphonic acid or hydroxypropane-sulphonicacid.

The salts of the compounds of formula I with acids and bases which arenot pharmaceutically acceptable form another aspect of the invention.These salts are intermediate compounds of use in the preparation of thecompounds of the invention. This is because the compounds of theinvention can be isolated as intermediates in the form of one of theirnon-pharmaceutically acceptable salts, before conversion to apharmaceutically acceptable compound.

A first group of preferred compounds is composed of the compounds offormula I in which X represents an oxygen atom.

Preference is more particularly given, among the compounds of theinvention, to those in which n represents 2 or 3 and better still thosein which n is 2.

Another group of preferred compounds is composed of the compounds inwhich Ar represents unsubstituted pyridyl, unsubstituted pyrimidinyl oroptionally substituted phenyl. When Ar represents substituted phenyl,the phenyl group preferably carries one or two substituents chosen from(C₁-C₆)alkoxy, halogen, phenoxy, trifluoromethyl and benzyloxy. Betterstill, when Ar represents substituted phenyl, the phenyl group issubstituted in the meta position by a (C₁-C₆)alkoxy group, a phenoxygroup, a trifluoromethyl group or a halogen atom, such as a fluorine orchlorine atom.

Another group of preferred compounds is composed of the compounds offormula I in which i represents 1 or 0, preferably 0.

According to a preferred alternative form of the invention, when i is 1,the —CH₂—COOH group is situated in the ortho position with regard to thechain

and the Z substituent is in the para position with respect to this samechain.

A final group of preferred compounds is composed of the compounds offormula I in which the —CH₂—COOH group is situated in the para positionon the phenyl group with respect to the chain

The invention also relates to two processes for the preparation of thecompounds of formula I.

According to a first process, an aromatic compound of formula II:

in which Z, X and i are as defined above for the formula I and P₁ is aprotective group for a carboxyl functional group, is reacted with apiperazine of formula III:

in which n and Ar are as defined above for the formula I and Grp₁ is aleaving group.

Among the protective groups for carboxyl functional groups, thosegenerally described in Protective Groups in Organic Synthesis, Greene T.W. and Wuts P. G. M., published by John Wiley and Sons, 1991, and inProtective Groups, Kocienski P. J., 1994, Georg Thieme Verlag, may besuitable. It is possible, by way of example, to envisage the protectionof the carboxyl functional group in the ester form: in this case, P₁represents (C₁-C₆)alkyl.

A halogen atom (for example chlorine or bromine), a(C₆-C₁₀)arylsulphonyloxy group, in which the aryl group is optionallysubstituted by one or more (C₁-C₆)alkyl groups, or a(C₁-C₆)alkylsulphonyloxy group, in which the alkyl group is optionallysubstituted by one or more halogen atoms, may be selected as example ofa Grp₁ group.

The operating conditions for the reaction of the compound II with thepiperazine III will be easily determined by a person skilled in the art,this reaction being a nucleophilic substitution.

The reaction of the compound II with the piperazine III isadvantageously carried out in a polar aprotic solvent in the presence ofa base.

Examples of appropriate solvents are acetonitrile, dimethylformamide,acetone, dimethyl sulphoxide and halogenated hydrocarbons, such asdichloromethane or dichloroethane.

Use may be made, as particularly preferred base, of potassium carbonate.

According to a preferred embodiment, the reaction of II with III iscarried out at a temperature of 50 to 120° C., for example at reflux ofacetonitrile, when the latter is chosen as solvent, in the presence ofan alkali metal iodide, such as potassium iodide.

The amount of potassium iodide which has to be used is variable anddepends essentially on the nature of the reactants, on the nature of thesolvent and on the reaction temperature.

A catalytic amount of potassium iodide (less than 1 molar equivalentwith respect to the compound II) is generally sufficient.

The reaction of the compound II with the compound III is stoichiometric.However, it may be possible to carry out the reaction in the presence ofa slight excess of the piperazine III, in such a way that the molarratio of III to II will generally be between 1 and 1.2.

The reaction of the compound II with the piperazine III leads to acompound of formula IV:

in which P₁, X, Z, i, n and Ar are as defined above, which compound isconverted to a compound of formula I by deprotection of the carboxylfunctional group.

The deprotection methods are those commonly used in the art. They are,for example, described in Protective Groups in Organic Synthesis, GreenT. W. and Wuts P. G. M., published by John Wiley and Sons, 1991, and inProtective Groups, Kocienski P. J., 1994, Georg Thieme Verlag.

When P₁ represents (C₁-C₆)alkyl, the deprotection can involve thesaponification of the ester functional group, for example by the actionof dilute sodium hydroxide solution.

The compounds of formula II are generally commercially available oreasily prepared by following known techniques.

The compounds of formula III can be prepared by reaction of a piperazineof formula V:

in which Ar is as defined above, with a compound of formula VIII:

Grp₁—(CH₂)_(n)—T  VIII

where Grp₁ is as defined above and T is a leaving group identical to ordifferent from Grp₁ and preferably a better nucleofuge than Grp₁,

A person skilled in the art knows in particular that a leaving groupbecomes increasingly labile as the corresponding negatively chargedspecies resulting from the heterolytic cleavage of the bond increases instability. In this particular instance, T⁻ must be more stable than Grp₁⁻ in order for T to be a better nucleofuge than Grp₁.

According to a preferred alternative form of the invention, Grp₁ is achlorine atom and T is a bromine atom.

The reaction of V with VIII is preferably carried out in a polar aproticsolvent chosen from those defined above, at a temperature of between 15and 80° C., preferably between 15 and 35° C., for example at roomtemperature (20 to 25° C.). Dimethylformamide is preferred, by way ofsolvents.

The reaction of the piperazine V with the compound VIII advantageouslytakes place in the presence of a base, such as potassium carbonate.

Another process of for the preparation of the compounds of formula Iconsist in reacting a piperazine of formula V

in which Ar is as defined above for the formula I, with a carboxylderivative of formula VI

in which n, X, Z and i are as defined above for the formula I, P₂ is aprotective group for a carboxyl functional group and Grp₂ represents aleaving group. P₂ may take any one of the meanings of P₁ above. Just asfor P₁, it is preferable for P₂ to represent (C₁-C₆)alkyl. Grp₂ is aleaving group, the meaning of which is not critical according to theinvention. Grp₂ can usually represent a halogen atom, a (C₆-C₁₀)aryl-sulphonyloxy group, in which the aryl part is optionallysubstituted by one or more (C₁-C₆)alkyl groups, or a(C₁-C₆)alkylsulphonyloxy group, in which the alkyl group is optionallysubstituted by one or more halogen atoms.

The reaction of the piperazine V with the compound VI may be carried outin any one of the polar aprotic solvents defined above, preferably inacetonitrile. The yields and the kinetics of the reaction are markedlyimproved when the reaction is carried out in the presence of a base andin particular in the presence of potassium carbonate.

The reaction may be carried out at a temperature of between 50 and 120°C., for example at reflux of the acetonitrile, when the latter acts assolvent.

By way of example, the piperazine of formula V is reacted with at leastone equivalent of the compound of formula VI, in acetonitrile, in thepresence of 1.5 to 3 equivalents of K₂CO₃ with respect to the piperazineof formula V. The molar ratio of the compound of formula VI to thepiperazine V is advantageously between 1 and 1.5, preferably between 1and 1.2.

According to a preferred embodiment of the invention, the reaction of Vwith VI is carried out in the presence of an alkali metal iodide, suchas potassium iodide. It can be of use to use up to 1 equivalent ofalkali metal iodide with respect to the amount of piperazine V. Thus,the molar ratio of alkali metal iodide to the piperazine V may varybetween 0.1 and 1.5 equivalents.

The reaction of the piperazine V with the compound VI results in acompound of formula VII:

in which n, X, Z, Ar, i and P₂ are as defined above, which compound isconverted to a compound of formula I by deprotection of the carboxylfunctional group.

The operating conditions for the deprotection reaction will be easilydetermined by a person skilled in the art according to the nature of theP₂ group.

When P₂ represents (C₁-C₆)alkyl, the deprotection can involve thesaponification of the ester functional group, for example by the actionof dilute sodium hydroxide solution.

The compounds of formula V are commercially available or easily preparedfrom commercial compounds.

The compounds of formula VI are easily prepared by reaction of acompound of formula IX

in which P₂, X, Z and i are as defined above for the formula VI, with aderivative of formula X

A—(CH₂)_(n)—Grp₂  X

where n and Grp₂ are as defined above for the formula VI and Arepresents a leaving group identical to or different from Grp₂ andpreferably more nucleofugic than Grp₂. According to a preferredembodiment of the invention, A is a bromine atom and Grp₂ is a chlorineatom.

The operating conditions for this reaction will be easily determined bya person skilled in the art using his overall knowledge of organicchemistry.

The reaction of IX with X preferably takes place in a polar aproticsolvent in the presence of a base, at a temperature of between 15 and120° C.

By way of example, the compound IX may be reacted with 1 to 4equivalents, preferably 1.4 to 3 equivalents, of the derivative X inacetonitrile, as solvent, in the presence of 1.5 to 3.5 equivalents ofK₂CO₃ with respect to the amount of compound IX, at a temperature ofbetween 40 and 120° C. The molar ratio of K₂CO₃ to the compound X isadvantageously between 0.8 and 1.2.

The compounds of the invention are of use in the treatment ofpathologies associated with insulin-resistance syndrome (syndrome X).

Insulin resistance is characterized by a reduction in the action ofinsulin (cf. Presse Medicale, 1997, 26 (No. 14), 671-677) and isimplicated in a large number of pathological conditions, such asdiabetes and more particularly non-insulin-dependent diabetes (type IIdiabetes or NIDDM), dyslipidaemia, obesity, arterial hypertension andcertain microvascular and macrovascular complications, such asatherosclerosis, retinopathies and neuropathies.

Reference may be made, in this respect, to, for example, Diabetes, Vol.37, 1988, 1595-1607, Journal of Diabetes and its Complications, 1998,12, 110-119, or Horm. Res., 1992, 38, 28-32.

The compounds of the invention in particular exhibit a stronghypoglycaemic or hypolipidaemic activity.

Another subject-matter of the present invention is thereforepharmaceutical compositions comprising, as active principle, a compoundaccording to the invention.

The pharmacuetical compositions according to the invention can bepresented in forms intended for administration by the parenteral, oral,rectal, permucosal or percutaneous route.

They will therefore be presented in the form of injectable solutions orsuspensions or multi-dose bottles, in the form of coated or uncoatedtablets, of dragees, of capsules, including hard gelatin capsules, ofpills, of cachets, of powders, of suppositories or of rectal capsules,of solutions or of suspensions, for percutaneous use, in a polarsolvent, for permucosal use.

The excipients which are suitable for such administrations arederivatives of cellulose or micro-crystalline cellulose, alkaline earthcarbonates, magnesium phosphate, starches, modified starches or lactosefor the solid forms.

For rectal use, cocoa butter or polyethylene glycol stearates are thepreferred excipients.

For parenteral use, water, aqueous solutions, physiological saline orisotonic solutions are the most conveniently used vehicles.

The dosage can vary within wide limits according to the therapeuticindication and the administration route, as well as the age and theweight of the subject.

The invention therefore also relates to the use of the compounds offormula I in the preparation of medicaments intended for the treatmentof diabetes.

The following examples illustrate the preparation of the compounds offormula I and that of the intermediates of formulae III and VI.

In the continuation, the following abbreviations have been used:

NMR: nuclear magnetic resonance

δ: chemical shift

s: singlet

d: doublet

t: triplet

m: unresolved peak

IR: infrared.

A—EXAMPLE OF THE PREPARATION OF A COMPOUND OF FORMULA III Preparation of1-(2-chloroethyl)-4-phenylpiperazine

(III: Grp₁=Cl, n=2, Ar=C₆H₅)

358.52 g of 1-bromo-2-chloroethane are added to 80 ml of drydimethylformamide at 20° C. in a three-necked flask equipped with amechanical stirrer, followed by 138 g of potassium carbonate and 81.12 gof N-phenylpiperazine dissolved in 300 ml of dimethylformamide. Thereaction mixture is then stirred for 2 h 30 at room temperature. It issubsequently poured onto 1 liter of a saturated aqueous sodium chloridesolution and extracted with diethyl ether. The organic phases arecombined and evaporated. 67 g of a yellow oil are obtained, which oil ispurified on a silica cake by using ethyl acetate as eluent. NMR (200MHz), CDCl₃, δ ppm: 2.68 (t, 4H), 2.80 (t, 2H), 3.25 (t, 4H), 3.64 (t,2H), 6.93 (m, 3H), 7.28 (t, 2H) IR (cm⁻¹); film: 2677, 1593, 1297.

B—EXAMPLES OF THE PREPARATION OF COMPOUNDS OF FORMULA VI 1—Preparationof methyl [4-(2-chloroethoxy)-phenyl]acetate

(VI: Grp₂=Cl, n=2, i=0, P₂=CH₃)

100 g of methyl [4-hydroxyphenyl]acetate and 248.6 g of potassiumcarbonate are added, with mechanical stirring, to a three-necked flaskcontaining 900 ml of acetonitrile. The reaction mixture is brought to50° C. and 258.13 g of 1-bromo-2-chloroethane, dissolved in 250 ml ofacetonitrile, are added over 1 hour. The reaction mixture is thenbrought to reflux of the solvent for 48 h.

After filtering the reaction mixture, the solvent is evaporated. Theresidual oil is taken up in a mixture of water and diethyl ether. Theethereal phases are combined, washed with normal sodium hydroxidesolution and then washed several times with water. After drying andevaporating the solvent, a greyish oil is obtained which is thenpurified by distillation (boiling point at 0.1 mm of mercury=112-116°C.). NMR (200 MHz), CDCl₃, δ ppm: 3.60 (s, 2H), 3.70 (s, 3H), 3.82 (t,2H), 4.25 (t, 2H), 6.85 (d, 2H), 7.22 (d, 2H) IR (cm⁻¹); film: 2953,1736, 1513, 1243.

The intermediates of formula VI, VI.2 to VI.6, collated in the followingTable 1 are prepared and isolated in an analogous way.

TABLE 1 Position of the Intermediate CH₂-COOH M.p. (° C.)/ compoundgroup i Z n B.p. (° C.) VI. 2 p 0 / 2 B.p. = 112-116° C.^((a)) VI. 3 m 0/ 2 oil VI. 4 o 0 / 2 oil VI. 5 p 0 / 3 oil VI. 6 p 0 / 4 oil^((a))boiling point at 0.1 mm Hg

In the above table, o, m and p respectively mean ortho, meta and para.

The position of the —CH₂—COOH group is indicated with respect to the—O—(CH₂)_(n)—Cl chain.

The position of the Z substituent is also indicated with respect to the—O—(CH₂)_(n)—Cl chain.

C—EXAMPLES OF THE PREPARATION OF COMPOUNDS OF FORMULA I 1—Preparation of(4-{2-[4-(3-methoxyphenyl)-piperazin-1-yl]ethoxy}phenyl) acetic acid(Example 1)

[I: Ar=—C₆H₄—OCH₃, n=2, i=0]

34.6 g of 1-(3-methoxy)phenylpiperazine [sic], 74.52 g of potassiumcarbonate and 29.88 g of potassium iodide are added, with magneticstirring, to a three-necked flask containing 400 ml of acetonltrile.41.16 g of methyl [4-(2-chloroethoxy)phenyl]acetate, dissolved in 250 mlof acetonitrile, are subsequently introduced over 15 min. The reactionmixture is maintained at reflux of the solvent for 72 h. After returningto room temperature, the reaction mixture is filtered and the solvent isevaporated. The residue is taken up in a mixture of water and ethylacetate. The combined organic phases are then dried and then evaporated.48.79 g of an orangey oil are thus isolated.

400 ml of methanol and 189.2 ml of 1N sodium hydroxide solution areadded to the latter. The reaction mixture is then maintained for 2 h atreflux of the solvent. After evaporation of the solvent to dryness, theresidue is triturated several times with diethyl ether. After removingthe ethereal phases, 1 liter of water is added to the residue. Afterstirring for 10 min, 189.2 ml of 1N hydrochloric acid are added. A beigeprecipitate is formed. After filtering off this precipitate and washingwith water of the reaction mixture and then drying, 42 g of a solid areobtained. The recrystallization from ethanol at 95° C. [sic], 38 g ofthe title compound are obtained, the melting point of which is between156 and 158° C. NMR (200 MHz), d6-DMSO, δ ppm: 2.48 (t, 4H), 2.60 (t,2H), 2.95 (t, 4H), 3.35 (s, 2H), 3.60 (s, 3H), 3.95 (t, 2H), 6.30 (m,3H), 6.70 (d, 2H), 7.0 (m, 3H) IR (cm⁻¹); KBr: 2957, 1716, 1597, 1604,1242.

The compounds of Examples 2 to 19 which appear in the following Table 2,where X in the formula below represents O:

are prepared by using one of the processes described above.

TABLE 2 Position of Melting point ¹H NMR (200 MHz) Ex. —CH₂—COOH i Z nAr (° C.) δ (ppm)  1 para 0 — 2

158-160 d6-DMSO: 2.48(t, 4H), 2.60(t, 2H), 2.9 (t, 4H), 3.35(s, 2H),3.60(s, 3H), 3.95 (t, 2H), 6.30(m, 3H), 6.70(d, 2H), 7.0 (m, 3H)  2 para0 — 2

163 d6-DMSO: 2.54(t, 4H), 2.62(t, 2H), 3.0 (t, 4H), 3.36(s, 2H), 3.98(t,2H), 6.68 (t, 1H), 6.80(t, 4H), 7.04(m, 4H)  3 ortho 0 — 2

74-76 d6-DMSO: 2.50(s, 4H), 2.65(t, 2H), 3.07 (s, 4H), 3.40(s, 2H),3.62(s, 3H), 4.05 (s, 2H), 6.30(m, 3H), 6.95(m, 5H)  4 meta 0 — 2

110-111 d6-DMSO: 2.45(s, 4H), 2.95(s, 4H), 3.35 (s, 2H), 3.50(s, 3H),3.90(t, 2H), 6.20 (m, 3H), 6.62(d, 3H), 6.91(m, 2H)  5 para 0 — 2

130 d6-DMSO: 2.72(s, 4H), 2.88(t, 2H), 3.20 (s, 4H), 3.55(s, 2H),4.15(t, 2H), 5.12 (s, 2H), 6.60(s+d, 3H), 7.0(d, 2H), 7.25 (m, 3H),7.50(m, 5H), 12.30(s, 1H)  6 para 0 — 2

130-132 CDCl3 [sic]: 2.77(m, 6H), 3.13(d, 4H), 3.35(s, 2H), 3.96(t, 2H),6.67(m, 5H), 7.03(m, 3H), 10.35(s, 1H)  7 para 0 — 2

162-164 d6-DMSO: 2.65(s, 4H), 2.77(t, 2H), 3.07 (s, 4H), 3.55(s, 2H),3.73(s, 3H), 4.11 (t, 2H), 6.95(m, 6H), 7.22(d, 2H)  8 para 0 — 2

160-163 CDCl3 [sic]: 2.7(m, 6H), 3.12(m, 4H), 3.40 (s, 2H), 4.0(t, 2H),6.50(m, 5H), 7.00 (m, 8H), 7.82(s, 1H)  9 para 0 — 2

204-206 (2HCl) d6-DMSO: 3.35(m, 12H), 3.75(s, 3H), 4.45 (s, 2H), 6.90(m,6H), 7.15(d, 2H), 9.40 (s, 2H), 11.65(s, 1H) 10 para 0 — 2

134-136 d6-DMSO: 2.51(s, 4H), 2.65(t, 2H), 3.15 (s, 4H), 3.40(s, 2H),4.0(t, 2H), 6.75 (d, 2H), 6.95(m, 5H), 7.08(t, 1H) 11 para 0 — 2

140 d6-DMSO: 2.67(s, 4H), 2.75(t, 2H), 3.18 (s, 4H), 3.50(s, 2H),4.10(t, 2H), 5.12 (s, 2H), 6.45(m, 3H), 6.90(d, 2H), 7.20 (m, 5H),7.45(t, 1H), 7.65(t, 1H) 12 para 0 — 2

132-134 d6-DMSO: 2.56(t, 4H), 2.77(t, 2H), 3.50 (d, 6H), 4.10(t, 2H),6.39(t, 1H), 6.87 (m, 3H), 7.22(d, 2H), 7.58(t, 1H), 8.14 (d, 1H),12.85(s, 1H) 13 para 0 — 2

153-154 CDCl3 [sic]: 2.95(t, 4H), 3.10(t, 2H), 3.64(s, 2H), 4.09(t, 4H),4.24(t, 2H), 6.59(t, 1H), 6.83(d, 2H), 7.28(d, 2H), 8.44(d, 2H), 9.22(s,1H) 14 para 0 — 4

113-115 CDCl3 [sic]: 1.75(s, 4H), 2.73(s, 2H), 2.95(s, 4H), 3.37(s, 4H),3.60(s, 2H), 3.85(s, 5H), 6.50(m, 3H), 6.80(d, 2H), 7.25(q, 3H), 8.30(s,1H) 15 para 0 — 2

135-137 CDCl3 [sic]: 2.82(s, 6H), 3.05(s, 4H), 3.40(s, 6H), 4.0(s, 2H),6.42(m, 2H), 6.67(t, 3H), 7.10(d, 2H), 11.80(s, 1H) 16 para 0 — 3

162-164 d6-DMSO: 1.90(t, 2H), 2.47(s, 6H), 3.10 (s, 4H), 3.45(s, 2H),3.65(s, 3H), 3.95 (t, 2H), 6.40(m, 3H), 6.85(d, 2H), 7.15 (m, 3H) 17para 0 — 2

148 d6-DMSO: 0.83(d, 6H), 1.85(m, 1H), 2.44 (s, 4H), 2.74(t, 2H),3.13(s, 4H), 3.34 (s, 2H), 3.55(d, 2H), 3.94(t, 2H), 6.27 (m, 3H),6.74(d, 2H), 6.98(m, 3H) 18 para 0 — 2

153-154 d6-DMSO: 1.14(t, 3H), 2.46(s, 4H), 2.58 (t, 2H), 2.96(s, 4H),3.35(s, 2H), 3.81 (q, 2H), 3.94(t, 2H), 6.27(m, 3H), 6.74 (d, 2H),6.92(m, 3H) 19 para 0 — 2

160-162 d6-DMSO: 2.65(s, 4H), 2.79(t, 2H), 3.52 (s, 2H), 3.59(s, 4H),4.11(t, 2H), 6.92 (d, 2H), 7.18(m, 4H), 7.50(d, 1H), 7.78 (d, 1H),12.30(s, 1H)

Likewise, the following compound 20 is prepared by employing a processanalogous to those illustrated above:

which compound has a melting point of 142° C. and is characterized bythe following soectral data: d6-DMSO: 2.43 (t, 6H), 2.99 (t, 6H), 3.42(s, 2H), 3.59 (s, 3H), 6.32 (m, 3H), 7.11 (m, 5H).

The results of a pharmacological study will be given below.

Study of the Antidiabetic Activity in the Rat

The antidiabetic activity of the compounds of formula I by the oralroute was determined on an experimental model of non-insulin-dependentdiabetes induced in the rat by streptozotocin.

The model of non-insulin-dependent diabetes is obtained in the rat by aneonatal injection (on the day of birth) of streptozotocin.

The diabetic rats used are 8 weeks old. The animals are kept, from theday of their birth to the day of the experiment, in an animal house at aregulated temperature of 21 to 22° C. and are subjected to a fixed cycleof light (from 7 h to 19 h) and of darkness (from 19 h to 7 h). Theirdiet consisted of a maintenance diet; water and food were provided “adlibitum”, with the exception of the 2 hours of fasting preceding thetests, where food is withdrawn (post-absorptive state).

The rats are treated by the oral route, during the day, with the testproduct. Two hours after the final administration of the product and 30minutes after anaesthetizing the animals with sodium pentobarbital(Nembutal®), a 300-μl blood sample is withdrawn at the end of the tailin order to determine the glycaemia.

The results obtained are collated in Table 3.

These results are expressed as a percentage of change in the glycaemia:

at D1 (after treatment for 1 day) with respect to D0 (before treatment);and

at D4 (after treatment for 4 days) with respect to D0 (before treatment)for 2 different administration doses (20 mg/kg/day and 200 mg/kg/day) ofactive principle.

TABLE 3 Dose administered Dose administered 20 mg/kg/day 200 mg/kg/dayCompound % of % of % of % of of glycaemia glycaemia glycaemia glycaemiaExample at D1 at D4 at D1 at D4 1 −8 −10 −24 −34 4 −2 −16 −20 −24 6 2−12 −2 −19 8 9 −6 19 −18 9 −2 3 1 −25 10  −26 −13 −30 −27 13  −10 −10−23 −23

These results show the effectiveness of the compounds of formula I ininducing a decrease in the glycaemia in the diabetic animals.

Study of the Hypolipidaemic Activity in the Rat

The hypolipidaemic activity of the compounds of formula I by the oralroute was determined on an experimental model of non-insulin-dependentdiabetes induced in the rat by streptozotocin.

The model of non-insulin-dependent diabetes is obtained in the rats by aneonatal injection (5 days after birth) of streptozotocin.

The diabetic rats used are 6 months old. The animals are kept, from theday of their birth to the day of the experiment, in an animal house at aregulated temperature of 21 to 22° C. and are subjected to a fixed cycleof light (from 7 h to 19 h) and of darkness (from 19 h to 7 h).

Their diet consisted of a maintenance diet; water and food were provided“ab [sic] libitum”, with the exception of the 18 hours of fastingpreceding the withdrawals of the blood samples on which the lipidbalances will be carried out.

The rats are treated by the oral route with the compound of Example 1for 7 days. A 300-μl sample is withdrawn 18 h after the finaladministration of this compound.

The total cholesterol was quantitatively determined by the CHOE/CHOD/PODTrinder method as an end point (Instrumentation Laboratory reagent[lacuna] on a Monarch plus analyser (Instrumentation Laboratory).

The total triglycerides were quantitatively determined by theGPO/Trinder method as an end point (Sigma Diagnostic reagent) on aMonarch analyser (Instrumentation Laboratory).

CONDITIONS TOTAL TOTAL FOR CARRYING CHOLESTEROL TRIGLYCERIDES OUT THETEST (mg/dl) (mg/dl) In the absence of 90 167 treatment By treatmentwith a 79 102 compound of Example 1

These results clearly demonstrate the hypolipidaemic activity of thecompounds of the invention.

What is claimed is:
 1. A compound of formula I:

in which: n represents 2, 3, 4, 5, or 6: X represents O or S; Arrepresents phenyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl orbenzimidazolyl, optionally substituted by one or more radicals chosenfrom (C₁-C₆)alkoxy; halogen; (C₆-C₁₀) aryloxy;(C₆-C₁₀)aryl-(C₁-C₆)alkoxy in which the aryl part is optionallysubstituted by halogen, (C₁-C₆)alkyl or (C₁-C₆)alkoxy; and (C₁-C₆) alkylsubstituted by one or more halogen atoms; i represents 0, 1, 2, 3 or 4;and each Z group independently represents a halogen atom; or an additionsalt thereof with a pharmaceutically acceptable base or acid.
 2. Acompound according to claim 1, in which X represents an oxygen atom. 3.A compound according to claim 1, wherein n represents 2 or
 3. 4. Acompound according to claim 1, wherein Ar represents pyridyl;pyrimidinyl; benzoxazolyl; benzothiazolyl; benzimidazolyl; phenyl; orphenyl substituted by one or more radicals chosen from (C₁-C₆) alkoxy;halogen; phenoxy; trifluoromethyl and benzyloxy.
 5. A compound accordingto claim 1, wherein Ar represents phenyl substituted in the metaposition by (C₁-C₆) alkoxy, a halogen atom, phenoxy or trifluoromethyl.6. A compound according to claim 1, wherein i represents
 0. 7. Acompound according to claim 1, wherein the —CH₂—COOH group is in thepara position on the phenyl group with respect to the chain:


8. A process for preparation of a compound according to claim 1,comprising reacting an aromatic compound of formula II:

in which Z, X and i are as defined in claim 1 for the formula I and P₁is a protective group for carboxyl functional group, with a piperazineof formula III:

in which Ar and n are as defined in claim 1 for the formula I and Grp₁is a leaving group, to obtain a compound of formula IV:

in which P₁, X, Z, i, n and Ar are as defined above, and converting thecompound of formula IV to a compound of formula I by deprotection of thecarboxyl functional group.
 9. A process for preparation of a compoundaccording to claim 1, comprising: reacting a piperazine of formula V:

in which Ar is as defined in claim 1 for the formula I, with a carboxylderivative of formula VI

in which n, Z, X and i are as defined in claim 1 for the formula I, P₂represents a protective group for carboxyl functional group and Grp₂represents a leaving group, to obtain a compound of formula VII:

in which n, X, Z, Ar, i and P₂ are as defined above, and converting thecompound of formula VII to a compound of formula I by deprotection ofthe carboxyl functional group.
 10. A pharmaceutical compositioncomprising one or more compounds according to claim 1, in combinationwith at least one pharmaceutically acceptable excipient.
 11. A methodfor the treatment of pathologies associated with insulin-resistancesyndrome, comprising administering to a patient in need thereof aneffective amount of a compound according to claim
 1. 12. A methodaccording to claim 11, wherein said patient is suffering from diabetes,dyslipidaemia, obesity, arterial hypertension, neuropathies,retinopathies or atherosclerosis.
 13. A compound according to claim 3,wherein n is
 2. 14. A compound according to claim 1, wherein the arylpart of aryloxy and arylalkoxy is phenyl or naphthyl.
 15. A compoundaccording to claim 1, wherein Ar is mono-, di- or tri-substitutedphenyl.
 16. A compound according to claim 1, wherein Ar is unsubstitutedpyridyl, unsubstituted pyrimidinyl, unsubstituted phenyl, or substitutedphenyl.
 17. A compound according to claim 1, wherein Ar is phenyl having1 to 2 substituents selected from (C₁-C₆) alkoxy, halogen, phenoxy,trifluoromethyl, and benzyloxy.
 18. A compound according to claim 1,wherein Ar is phenyl substituted in the meta position by (C₁-C₆) alkoxy,fluorine, chlorine, phenoxy or trifluoromethyl.
 19. A compound accordingto claim 1, wherein i is 1 or
 0. 20. A compound according to claim 1,wherein i is 1 and the —CH₂—COOH group is in the ortho position withregard to the chain

and Z is the para position with respect to this chain.
 21. A compound offormula I:

in which: n represents 2, 3, 4, 5, or 6: X represents O or S; Arrepresents phenyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl orbenzimidazolyl, optionally substituted by one or more radicals chosenfrom (C₁-C₆) alkoxy; halogen; (C₆-C₁₀) aryloxy; (C₆-C₁₀)aryl-(C₁-C₆)alkoxy in which the aryl part is optionally substituted by halogen,(C₁-C₆) alkyl or (C₁-C₆) alkoxy; and (C₁-C₆) alkyl substituted by one ormore halogen atoms; i represents 0, 1, 2, 3 or 4; and each Z groupindependently represents a halogen atom; or an addition salt thereofwith a base or acid.
 22. A compound according to claim 1, wherein the—CH₂—COOH group is in the para or ortho position with respect to thechain


23. A compound according to claim 22, wherein the —CH₂—COOH group is inthe para position with respect to the chain